Acute and late morbidity in the treatment of advanced bladder carcinoma with accelerated radiotherapy, carbogen, and nicotinamide

Abstract

BACKGROUND Accelerated radiotherapy combined with carbogen and nicotinamide (ARCON) to overcome tumor hypoxia and cell proliferation achieved high tumor control and survival in Phase II studies of patients with advanced head and neck and bladder carcinomas. Thus, morbidity and treatment outcomes from the latter study were analyzed to evaluate the therapeutic potential of ARCON. METHODS Acute and late morbidity was assessed in 105 patients with high‐grade superficial or muscle‐invasive bladder carcinoma who were given accelerated radiotherapy (50–55 grays in 4 weeks) with carbogen alone or with ARCON. Urinary dysfunction was scored based on daytime frequency, nocturia, incontinence, dysuria, hematuria, and urgency. Bowel morbidity was based on stool frequency and consistency, rectal discharge, blood loss, and medication. Endpoints for treatment outcome were overall survival, disease‐free survival, and locoregional control. RESULTS Nearly all patients experienced reduced ability to retain urine beyond 2 hours, although 20–30% had almost normal function at night. Incidence of acute moderate or worse dysuria was 41% with ARCON and 56% with carbogen; 96% and 76% of patients, respectively, had bowel frequencies ≥ 3 times per day. By 10–12 weeks from the start of radiotherapy, acute reactions returned to baseline levels. At 3 years, the daytime frequency ≤ 2 times per hour was ≈ 75% in both arms. Incidence of severe hematuria (≤ 25%) and urinary urgency (≤ 16%) was much lower. No more than 6% of patients had severe bowel morbidity. With most assays, the differences between schedules were not significant either for acute or late morbidity. Local tumor control and survival rates at 3 years were 53% and 43%, respectively, for ARCON, similar to the rates for carbogen alone. CONCLUSIONS Historical comparisons suggested no overt increase in normal tissue radiosensitivity when adding carbogen and nicotinamide. Although, for some endpoints, the incidence of late sequelae was higher than expected, overall morbidity was no worse than reported by others. The data indicated that ARCON could achieve a therapeutic gain in patients with advanced bladder carcinoma. A Phase III, randomized, multicenter trial is underway currently in the United Kingdom to evaluate these findings. Cancer 2005. © 2005 American Cancer Society.

The magic of the hypoxia-signaling cascade

“…In non-smallcell lung cancer, there were no significant responses with ARCON [119]. Nevertheless, in bladder cancer, ARCON showed significant gains on local control, disease-free survival and overall survival compared with a group control [120].…”

Overcoming Physiologic Barriers to Cancer Treatment by Molecularly Targeting the Tumor Microenvironment

“…This approach aims to reduce both chronic, diffusion-limited hypoxia through the use of carbogen gas breathing and acute, perfusion-limited hypoxia through the use of the vasoactive drug nicotinamide to render tumors more radiosensitive. In early clinical testing, increased tumor control rates have been observed in phase II trials in bladder cancer (55) and head and neck cancer (54), and phase III trials are currently ongoing.…”

Radiation Cystitis: Acute and Chronic

“…The cumulative incidence of grade 3 or higher urinary AEs after bladder RT is 6-17 % with follow-up ranging from 29 to 76 months [31]. Urinary blood clots can occur in 18 %, incontinence in 20 %, and urinary frequency more than once an hour in 50 % at 3 years [32]. Two series report the incidence of grade 3-4 AEs collectively as 14.5 and 25 %; when separately recorded, grade 4 AEs occur in 0-3 % [30,33].…”